Japanese version of The Cancer Genome Atlas,JCGA, established using fresh frozen tumors obtained from 5143 cancer patients

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.     

Porphyromonas gingivalis fimbriae induce unique dendritic cell subsets via Toll-like receptor 2

Backgound and Objective:  Dendritic cells (DCs) play a critical role in the activation of T cells as well as in shaping immune responses. We have reported previously that Porphyromonas gingivalis lipopolysaccharides ( Pg LPS) induced a CD14⁺CD16⁺ DC subset with a weak immuno-stimulatory activity. In contrast, Escherichia coli LPS ( Ec LPS) induced fully matured DCs with strong immunostimulatory activities. Since Pg LPS as well as Pg fimbriae have been indicated to work as Toll-like receptor (TLR) 2 ligands, we speculate that the TLR usage of bacterial antigens may be critical for DC maturation.
Material and Methods:  We investigated the effect of Pg fimbriae on the phenotype and function of human peripheral blood DCs in comparison with a TLR2 ligand, peptidoglycan, and a TLR4 ligand, Ec LPS.
Results:  Flow cytometry revealed that Pg fimbriae and peptidoglycan but not Ec LPS induced CD14 and CD16 expression on peripheral blood DCs (CD14⁻CD16⁻). A monoclonal antibody against TLR2 abrogated this induction, but an antibody against TLR4 had no effect. Dendritic cells stimulated with Pg fimbriae had a weaker capability to induce allogenic T cell proliferation and exhibited a weaker production of interleukin-8 and regulated upon activation, normal T cell expressed and secreted (RANTES) than DCs stimulated with Ec LPS.
Conclusion:  These results indicate that different TLR usage affects mature DC phenotype and function and is thus crucial to the regulation of immunity to the pathogen.     

Secondary craniofacial reconstruction of huge frontoethmoidal encephalomeningocele after primary neurosurgical repair

Frontoethmoidal encephalomeningocele is a congenital herniation of intracranial contents, including meninges, brain and part of the ventricle, through a bony defect in the skull at the junction of the frontal and ethmoid bones. Management involves meticulous preoperative assessment using computed tomography scans and magnetic resonance imaging, and surgical repair of the central nervous system, skeletal deformities of the orbit, downward displacement of the medial canthi, upward displacement of the eyebrows, and nasal deformities. Frontoethmoidal encephaloceles are best operated on via a craniofacial approach which enables repair of the central nervous system and skeletal deformities in one stage. However, a two-stage reconstruction must be considered when a prolonged operative time is expected or the patient's general condition increases the risks. There have only been a few reports of two-stage reconstructions. We performed a two-stage reconstruction of a huge frontoethmoidal encephalomeningocele, with neurosurgical repair during the first procedure and craniofacial reconstruction during the second procedure. We report on the surgical procedures and the problems encountered.     

Cleavage of PDGF receptor on periodontal ligament cells by elastase

Human leukocyte elastase, a neutrophil serine protease, is considered to be a potential immunoregulatory protease. Since the PDGF receptor (PDGFR) on periodontal ligament (PDL) cells is a crucial element for various functions, such as wound healing in periodontal tissue, we investigated the effect of elastase on the expression of PDGFR on PDL cells by flow cytometry and Western blotting. We found that PDGFR-alpha disappeared with an increasing dose of elastase, and PDGFR-beta was degraded into several fragments. Elastase degraded both receptors on fixed cells, indicating that the degradation resulted from direct proteolysis on the cell surface. Elastase also then disturbed the phosphorylation of ERK1/2, JNK/SARK, and p38, triggered by PDGF-AA and PDGF-BB, suggesting that elastase inhibited PDGFR-dependent cell activation in PDL cells. These results suggest that elastase may modulate the PDGF-mediated activity of PDL cells during periodontal wound healing.     

A study on tooth mobility following periodontal surgery

The purpose of this study was to evaluate the quantitative changes in tooth mobility before and after periodontal surgery using a tooth mobility tester. The tester was so designed as to be able to measure the cycle of sympathetic vibrations produced when a tooth was tapped with a impact hammer. Initially the degrees of tooth mobility, which were clinically classified from 0 to 3, were observed and the mode of mobility was assessed by the tester. Then, we examined the changes of tooth mobility after flap surgery. The following is a summary of findings.

Esophagogastric tube reconstruction with stapled pseudo-fornix in laparoscopic proximal gastrectomy: a novel technique proposed for Siewert type II tumors

Purpose

The incidence of adenocarcinoma of the esophagogastric junction is increasing, but laparoscopic proximal gastrectomy is not widely accepted due to the absence of a standardized technique of reconstruction. This report describes a novel technique of esophagogastric tube reconstruction in laparoscopic proximal gastrectomy for Siewert type II tumors.

Methods

Laparoscopic proximal gastrectomy, sometimes with transhiatal distal esophagectomy, was performed. After a perigastric, suprapancreatic, and lower thoracic paraesophageal lymphadenectomy, a gastric tube of 35-mm width was prepared. An esophagogastric tube anastomosis with pseudo-fornix was made with a no-knife linear stapler to prevent postoperative reflux esophagitis.

Results

Fifteen patients with Siewert type II tumors underwent this operation. They included six patients with early-stage cancer, six at high risk for transhiatal total gastrectomy due to several comorbidities, and three who needed palliative tumor resection. The mean operation time was 315 min. One postoperative anastomotic leak was treated conservatively, and three anastomotic stenoses were resolved with endoscopic balloon dilatation. Postoperative 1-year follow-up endoscopy revealed four cases of reflux esophagitis that were well controlled by medication.

Conclusions

This new technique of reconstruction was feasible. With the advantage of a gastric tube, a tension-free anastomosis was possible even for bulky tumors that needed lower esophagectomy. Although long-term follow-up and a larger number of patients are required to evaluate long-term functional outcomes and oncological adequacy, our procedure has the potential of becoming a treatment of choice for early-stage Siewert type II tumors and/or for some selected high-risk patients who need tumor resection.     

Antigen‐specific airway IL‐33 production depends on FcγR‐mediated incorporation of the antigen by alveolar macrophages in sensitized mice

Although interleukin (IL)‐33 is a candidate for the aggravation of asthma, the mechanisms underlying antigen‐specific IL‐33 production in the lung are unclear. Therefore, we analysed the mechanisms in mice. Intra‐tracheal administration of ovalbumin (OVA) evoked increases in IL‐33 and IL‐33 mRNA in the lungs of both non‐sensitized and OVA‐sensitized mice, and the increases in the sensitized mice were significantly higher than in the non‐sensitized mice. However, intra‐tracheal administration of bovine serum albumin did not increase the IL‐33 level in the OVA‐sensitized mice. Depletion of neither mast cells/basophils nor CD4⁺ cells abolished the OVA‐induced IL‐33 production in sensitized mice, suggesting that the antigen recognition leading to the IL‐33 production was not related with either antigen‐specific IgE‐bearing mast cells/basophils or memory CD4⁺ Th2 cells. When a fluorogenic substrate‐labelled OVA (DQ‐OVA) was intra‐tracheally administered, the lung cells of sensitized mice incorporated more DQ‐OVA than those of non‐sensitized mice. The lung cells incorporating DQ‐OVA included B‐cells and alveolar macrophages. The allergic IL‐33 production was significantly reduced by treatment with anti‐FcγRII/III mAb. Depletion of alveolar macrophages by clodronate liposomes significantly suppressed the allergic IL‐33 production, whereas depletion of B‐cells by anti‐CD20 mAb did not. These results suggest that the administered OVA in the lung bound antigen‐specific IgG Ab, and then alveolar macrophages incorporated the immune complex through FcγRII/III on the cell surface, resulting in IL‐33 production in sensitized mice. The mechanisms underlying the antigen‐specific IL‐33 production may aid in development of new pharmacotherapies.     

The Vidian Canal: Radiological Features in Japanese Population and Clinical Implications

The vidian canal (VC), a bony tunnel in which the vidian artery and nerve pass, has been widely known as an important landmark to identify the anterior genu of the petrous carotid artery (AGPCA) especially during lateral extended endoscopic endonasal approachs (LEEEAs). The objectives of this study in the Japanese population are to describe the radiological anatomic features and relationships between VC and its surrounding structures, and discuss the clinical implications. We studied 231 high-resolution computed tomography (CT) scans with a slice thickness of 0.5 mm. All the patients had known sellar or parasellar pathologies but without any involvement of VC. The following VC-related parameters were examined: its length, relationship to AGPCA, course from the pterygopalatine fossa to the carotid canal, its position relative to the medial pterygoid plate and pneumatization pattern of the sphenoid sinus. Mean length of VC is 14.6 mm. There is more tendency of straight-running VC compared to other populations. VC locates infero-lateral to AGPCA in all the cases. The protrusion of VC and the paraclival carotid artery to the sphenoid sinus, as well as well-pneumatization of the sinus is also observed more frequently in almost a half of the population. Surgeons who perform LEEEAs in Japanese patients must know these anatomical features. The characteristics particular to Japanese populations may facilitate better identification of VC and exposure to AGPCA intraoperatively.